Alzheimer's disease (AD) afflicts approximately 35 million people worldwide and is the most common cause of dementia in the elderly. There is an unmet medical need for new AD therapeutic development. Amyloid-beta (Abeta or Aβ) deposited in AD brains has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death observed in AD brains. Therefore, designing therapies targeting Abeta and downstream events has become a major effort in AD drug development. We have synthesized a class of tricyclic pyrone compounds (TPs). The lead compounds were found to have high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity. Administering the compounds either orally or intraperitoneally to young AD transgenic models in ‘preventive studies’ resulted in substantially reduced soluble and insoluble Abeta species in the brain and preserved memory and motor function. Furthermore, we have found that in addition to being able to block the toxicity and formation of both intraneuronal and extracellular Aβ aggregates, the lead TPs also increase cellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic placidity—these synergistic cellular actions could be potential mechanisms underlying in vivo effects.
As populations worldwide age and the number of subjects with Alzheimer's continues to expand, effective treatments are being actively pursued. To date, however, only a limited number of pharmacological agents heretofore have been identified as effective in treating symptoms of AD in a person suffering therefrom. The most prominent of these today are tacrine and donepezil hydrochloride, which are cholinesterase inhibitors active in the brain. Thus, there is a need in the art for additional therapeutic agents for treating Alzheimer's and other neurodegenerative disorders.